The following review of the background of the invention is merely provided to aid in the understanding of the present invention and neither it nor any of the references cited within it are admitted to be prior art to the present invention.
Management of nosocomial or community-acquired bacterial infections is becoming very difficult due to the emergence of bacteria resistant to one or multiple families of antibiotics. Unfortunately, the widespread and indiscriminant use of antibiotics has led to a rapid increase in the number of bacterial strains which are resistant to antibiotics. Most importantly, resistance has emerged among clinically important microorganisms which threaten the utility of the currently available arsenal of antibiotics. A global trend of increasing resistance to antibiotics, with wide variations according to geographical areas, is well documented by the World Health Organization and in the scientific literature.
There is a need for novel and effective antibiotics that are particularly active against microorganisms which are resistant to currently available drugs. For example, resistance of bacteria causing urinary tract infections to trimethoprim-sulfamethoxazole, β-lactams and fluoroquinolones is becoming a major factor in the management of such infections. Despite the use of nitrofuran antibiotics for several decades, mainly for the treatment of urinary tract infections, resistance to agents of this family has remained low (0-2%) in microorganisms most commonly encountered (Gupta K. Addressing antibiotic resistance. Dis Mon. 2003 February; 49(2):99-110; Nicolle LE. Urinary Tract Infection: Traditional pharmacologic therapies. 2003. February; 49(2):111-128).
U.S. Pat. Nos. 3,970,648, 3,973,021 and 3,974,277 disclose nitrofurans of the following formulae: 2-[2-(5-nitro-2-furyl)vinyl]-4-(anilino)quinazoline, 2-[2-(5-nitro-2-furyl)vinyl]-4-(p-hydroxyanilino)-quinazoline, 2-[2-(5-nitro-2-furyl)vinyl]-4-(o-hydroxyanilino)-quinazoline, and 2-[2-(5-nitro-2-furyl)vinyl]-4-(m-hydroxyanilino)-quinazoline. These patents teach the use of these compounds as pesticides and animal growth promotants for improving feed efficiency in animals such as poultry, swine and cattle. Although these molecules gained the property of being adequate edible feed additives for animal growth promotion compared to quinazoline molecules having the nitrofuran group directly attached to it (U.S. Pat. No. 3,542,784), a drawback of the compounds from the above patents (U.S. Pat. Nos. 3,970,648, 3,973,021 and 3,974,277) is that the patents teach that they are now devoid of activity against important pathogens such as Escherichia coli, Staphylococcus aureus and Salmonella. It would be desirable to obtain nitrofurans which provide significant improvement of potency and expand the antimicrobial spectrum of activity. This means that lower amounts of compounds are required for in vitro and in vivo (in animals) antimicrobial action against a wider variety of pathogens affecting animals and humans.
Besides, there are only a few nitrofuran antibiotics currently used in humans for the treatment of infectious diseases and one is known by the generic name nitrofurantoin (commercial names include: Macrobid, Macrodantin, Furadantin). It is used in adults and children to treat acute urinary tract infections and to prevent recurrent urinary tract infections. A drawback of nitrofurantoin is that it does not have good potency (i.e., relatively high amounts are required to exert its antibacterial activity) and it does not have a wide spectrum of antimicrobial activity, which limits the use of this compound in treating bacterial infections.
Novel nitrofurans with superior antimicrobial potency and improved pharmacological properties, would provide an alternative for the treatment of severe infections caused by antibiotic-susceptible and -resistant microorganisms.